Summary Cyanide is fundamentally a metabolic toxin. Although it has many known targets, many of its pathological consequences can be ascribed to inhibition of mitochondrial respiration through inactivation of Complex IV of the electron transport chain. Given this prominent role of metabolism in the pathophysiology of cyanide poisoning, we expect that modulators of metabolism might have potential as therapeutic countermeasures. In fact, this Center has recently discovered that the metabolite glyoxylate profoundly mitigates cyanide lethality in zebrafish, mice and rabbits. We propose to build upon this foundation by defining the metabolic functions of this and other agents and testing the hypothesis that redox imbalance underlies cyanide toxicity. We have further discovered that activators and substrates of the TCA cycle also confer cyanide resistance and propose to further develop such agents as therapeutics as well as complete our highly focused screen of metabolites and metabolic modulators. We also propose a series of mechanistic experiments to interrogate the extent to which Complex IV inhibition is the mechanism of cyanide toxicity and the organs that mediate that toxicity. These studies will synergize with experiments aimed at understanding the metabolic physiology of cyanide toxicity and the response to various mitigating approaches. We hypothesize that a deeper understanding of the metabolic basis of cyanide toxicity and mitigation will inform a rational approach to countermeasures and their appropriate application.